The role of chemicals in the etiology of cancer in man is a question demanding an early answer. The burden of such drugs, chemicals and environmental pollutants ingested and inhaled is unlikely to diminish in the near future. That the unborn child can be a victim has been tragically illustrated by the development of adenocarcinoma of the genital tract in teen-aged girls whose mothers had been treated with diethylstilbestrol while pregnant. We propose to continue our studies of the ontogeny of the mixed-function oxidase system, enzymes which can both activate and detoxify a number of chemical carcinogens, of which the polycyclic aromatic hydrocarbons, such as benzo(a)pyrene, have been most studied. The inducibility of aryl hydrocarbon hydroxylase (AHH), a mixed-function oxidase which metabolizes benzo(a)pyrene, is under genetic control and this Mendelian trait has been linked to a susceptibility to bronchongenic carcinoma in man. We will carry out a multifaceted study of developmental and genetic factors involved in chemical carcinogenesis, emphasizing in utero carcinogenesis. Mice that are either AHH inducible or non-inducible will be utilized, as well as a strain having a high incidence of spontaneous hepatomas. Another model system used will be human diploid fibroblasts in culture. Biochemical studies will include drug and benzo(a)pyrene metabolism in the basal and induced states and DNA damage and repair. Immunologic studies will focus on alpha-fetoprotein as a developmentally controlled possible mediator of immunosuppression. Morphologic studies will be performed to correlate cellular damage, regeneration and transformation with alterations in biochemical functions. These studies will be integrated so as to obtain new information and concepts regarding the interplay of genetic and environmental factors involved in determining the suceptibility of an individual to chemical carcinogens before birth.